UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

Nat Commun. 2023 Jul 5;14(1):3966. doi: 10.1038/s41467-023-39591-2.


KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Animals
  • CCAAT-Enhancer-Binding Proteins* / genetics
  • CCAAT-Enhancer-Binding Proteins* / metabolism
  • Cell Transformation, Neoplastic / genetics
  • DNA Methylation
  • Epigenesis, Genetic
  • Humans
  • Lung Neoplasms* / genetics
  • Mice
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitin-Protein Ligases* / metabolism


  • CCAAT-Enhancer-Binding Proteins
  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Ubiquitin-Protein Ligases
  • UHRF1 protein, human
  • Uhrf1 protein, mouse